Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections
Frederick G. Hayden, M.D., Albert D.M.E. Osterhaus, D.V.M., Ph.D., John J. Treanor, M.D., Douglas M. Fleming, F.R.C.G.P., Ph.D., Fred Y. Aoki, M.D., Karl G. Nicholson, M.D., Arthur M. Bohnen, M.D., Hilary M. Hirst, Oliver Keene, M.A., M.S., Kevin Wightman, B.S., for The GG167 Influenza Study Group
Background The sialic acid analogue zanamivir (GG167) is a selectiveinhibitor of influenza A and B virus neuraminidases. These viralenzymes are essential for the release of virus from infectedcells, and they may also reduce the inactivation of virus byrespiratory secretions. When administered experimentally directlyto the respiratory tract, zanamivir has potent antiviral effects.We assessed the therapeutic activity of zanamivir in adultswith acute influenza.
Methods We conducted separate randomized, double-blind studiesin 38 centers in North America and 32 centers in Europe duringthe influenza season of 1994–1995. A total of 417 adultswith influenza-like illness of <48 hours' duration were randomlyassigned to one of three treatments: 6.4 mg of zanamivir byintranasal spray plus 10 mg by inhalation, 10 mg of zanamivirby inhalation plus placebo spray, or placebo by both routes.Treatments were self-administered twice daily for five days.
Results Of 262 patients with confirmed influenzavirus infection(63 percent of all patients), the median length of time to thealleviation of all major symptoms was one day shorter (fourdays vs. five days) in the 88 patients given inhaled and intranasalzanamivir (P=0.02) and the 85 patients given inhaled zanamiviralone (P=0.05) than in the 89 patients given placebo. Amongthe infected patients who were febrile at enrollment and amongthose who began treatment within 30 hours after the onset ofsymptoms, the median time to the alleviation of major symptomswas four days in both zanamivir groups and seven days in theplacebo group (P<0.01). Viral titers of nasal washings inthe group given inhaled and intranasal zanamivir were significantlylower than those in the placebo group. The topically administeredzanamivir was well tolerated.
Conclusions In adults with influenza A or B virus infections,direct administration of a selective neuraminidase inhibitor,zanamivir, to the respiratory tract is safe and reduces symptomsif begun early.
Two general measures are available to reduce the impact of influenza:immunization with inactivated vaccines and antiviral prophylaxisand therapy with amantadine and rimantadine.1 The usefulnessof amantadine and rimantadine is limited by an antiviral spectrumrestricted to influenza A viruses, their uncertain effectivenessin severe influenza or in preventing complications, side effects,and the emergence of drug-resistant variants.2 Consequently,there is a continuing need for more effective antiviral agentsto manage influenza infections.
The sialic acid analogue zanamivir (GG167) is a potent, specificinhibitor of influenzavirus neuraminidase.3,4 This enzyme, essentialfor replication in vitro,5 cleaves terminal sialic acid residuesfrom glycoconjugates to allow the release of virus from infectedcells, prevent the aggregation of virus, and possibly reduceviral inactivation by respiratory mucus.6,7 Zanamivir inhibitsa range of influenza A and B viruses in vitro.8,9 Topicallyapplied zanamivir is active in animal models of influenza,3,8,10although systemically administered drug has little antiviralactivity. In adults experimentally inoculated with influenzaA virus, prophylactic intranasal zanamivir was highly protectiveagainst infection and febrile illness.11 Treatment beginningone day after viral challenge also reduced peak viral titersby a factor of approximately 100 and reduced the frequency offebrile illness by 85 percent. We undertook studies to determinewhether topical application of zanamivir would prove effectivein the treatment of naturally occurring acute influenza. Becauseinfluenza commonly involves the lower respiratory tract,12 bothintranasal and inhaled forms of the drug were tested.
Methods
Two parallel multicenter trials were conducted in North America(38 centers) and Europe (32 centers) during the 1994–1995influenza season. Both were randomized, double-blind, and placebo-controlledin design and tested the same regimen of drug treatment.
Patients
Previously healthy persons who were at least 18 years old (atleast 13 years in North America) with an acute influenza-likeillness of <48 hours' duration during documented influenzaviruscirculation in the community were enrolled. Illness was definedas the presence of fever and at least two other symptoms (headache,myalgia, cough, and sore throat). Suspected bacterial infectionor recent use of antimicrobial drugs, immunization with influenzavaccine for the current season, pregnancy or breast-feeding,concurrent use of intranasal or inhaled medications, and underlyingconditions for which influenza immunization is currently recommendedwere reasons for exclusion. Women of childbearing potentialwere enrolled if they were using an acceptable means of contraceptionand had a negative urine pregnancy test. Subjects provided writteninformed consent using a form approved by an appropriate institutionalreview or ethics committee.
Study Procedures
At enrollment, a medical history was obtained, a physical examinationwas conducted, and a complete blood count, blood chemical analyses,and urinalysis were performed. Serum for hemagglutination-inhibitiontests (performed at the University of Rochester, N.Y., or theNational Institute for Biological Standards and Control, UnitedKingdom) and nose and throat swabs or nasal washings for viralculture were also collected.
Patients were randomly assigned to receive one of three treatments:10 mg of zanamivir by inhalation by mouth plus 6.4 mg by intranasalspray, 10 mg of zanamivir by inhalation plus placebo nasal sprays,or placebo by both routes. Treatments were self-administeredtwice daily for five days. A Diskhaler device (Glaxo Wellcome,Ware, United Kingdom) was used to administer two inhalationsof a dry powder containing 20 mg of lactose and 5 mg of zanamivirby mouth. The aerodynamic mass median diameter of the micronizedpowder was estimated to be approximately 3.0 µM. Lactosealone served as the vehicle control. The nasal aqueous spraywas administered as two 0.1-ml sprays per nostril. Compliancewith the study medications was determined by having the patientskeep daily diaries chronicling treatment. Each patient was givena package of relief medications, which included acetaminophen,dextromethorphan hydrobromide, and pseudoephedrine.
The patients recorded their symptoms (nasal stuffiness or runnynose, sore throat, cough, muscle aches, tiredness or fatigue,headache, loss of appetite, and feverishness) on a diary cardeach morning and evening. Severity was rated on a four-pointscale in which a score of 0 indicated no symptoms, a score of1 mild symptoms, a score of 2 moderate symptoms, and a scoreof 3 severe symptoms. Patients also recorded their oral temperaturestwice daily and their ability to engage fully in usual dailyactivities. They returned one to three days after treatmentfor a follow-up examination, to provide laboratory samples,and to report any adverse experiences. They also returned duringconvalescence on days 21 to 28 for hemagglutination-inhibitionantibody testing.
At three centers (Rochester, N.Y.; Charlottesville, Va.; andWinnipeg, Manitoba), nasal washings were collected on days 2,4, 6, and 8 for titration of virus. Samples were frozen, andany that were initially culture-positive were cultured againin Madin–Darby canine-kidney cells to determine the mediantissue-culture infective dose of virus (log10 TCID50) per milliliterof sample.
Statistical Analysis
The primary clinical end point was the length of time to thealleviation of all major symptoms of influenza, as defined bythe absence of feverishness and the presence of no other majorsymptoms (headache, myalgia, cough, and sore throat), or onlymild ones, for at least 24 hours. For the analysis of this endpoint, the patients were grouped into 10 categories, from day1 to day 10 or later, according to the day on which their symptomsresolved. Patients who withdrew with no evidence of alleviationof symptoms were included in the "day 10 or later" category.13Patients with influenzavirus infection, defined by the recoveryof virus, a fourfold or greater rise in serum antibody titerson hemagglutination-inhibition testing, or both, were consideredable to be evaluated in the efficacy analysis. All patientswho received the study drug were assessed for adverse events.
The statistical-analysis strategy involved the combined useof nonparametric and model-based methods.14 Pairwise comparisonsof intranasal and inhaled zanamivir with placebo and of inhaledzanamivir with placebo were performed with an extended Mantel–Haenszeltest, with integer scores stratified according to the protocol.15Estimates and confidence intervals for treatment effects werebased on analysis of variance after allowance for effects dueto the study protocol and treatment. The two tests were viewedas belonging to a hierarchy; no adjustments for multiple comparisonswere made.
Prognostic factors identified as potentially influencing theefficacy of treatment included the study site (North Americavs. Europe), the type of influenzavirus, the duration of symptomsbefore entry into the study, and the presence of fever at entry(oral temperature, >37.8°C). Tests of the interactionof each of these covariates with treatment were performed withanalysis of variance. Where statistically significant interactionswere observed, further subgroup analyses were performed.
Secondary end points included the lengths of time to the resumptionof normal activities, to the alleviation of individual symptoms,to the loss of fever, and to the loss of detectable virus. Theviral shedding area under the curve (AUC) was also determined.11The secondary end points were analyzed in the same manner asthe primary end point, except for the viral shedding AUC, whichwas analyzed with analysis of covariance to allow for effectsdue to base line (day 1 value) and treatment. All analyses wereperformed with SAS systems and procedures.
Sample Size
The calculation of sample size was based on the assumption thatmajor symptoms would be alleviated by the sixth study day inapproximately 50 percent of influenzavirus-infected placeborecipients. A clinically relevant difference was defined asan increase in this fraction to 75 percent or greater. A sampleof 195 infected patients (65 per group) is required for a two-tailedtest of these proportions at the 5 percent level of significanceand 80 percent power.16 On the basis of an influenza-infectionrate of approximately 70 percent, each study was designed torecruit 273 patients. However, neither individually reachedits enrollment goal (111 infected patients in North Americaand 151 in Europe). Before the results were unblinded, we decidedto perform a combined analysis of the two studies. The resolutionof illness and effects of drug administration were similar inthe two trials.
Results
Patients
A total of 220 patients with suspected influenza were randomlyassigned to a treatment group in North American centers and197 in European centers (Table 1). Overall, 63 percent had laboratoryconfirmation of influenzavirus infection. The frequency of confirmedinfection was higher in European centers (77 percent) than inNorth American ones (50 percent), in part because of the greateruse of rapid antigen screening. Of the 262 influenza-positiveillnesses, 56 percent were due to influenza A virus and 44 percentto influenza B virus. The predominant strains in North Americawere H3N2 subtypes, whereas influenza B infections predominatedin Europe (Table 1). Most infected patients were culture-positiveat entry; the duration of illness before enrollment averaged31 hours in the three treatment groups. Other demographic characteristicsof enrolled patients and their severity of illness were generallysimilar (Table 1), although an excess of smokers was presentin the group assigned to intranasal and inhaled zanamivir.
Table 1. Characteristics of 262 Patients Infected with Influenza According to Treatment Center and Treatment Group.
One patient randomly assigned to the placebo group failed totake the study drug. Eight other patients in the placebo groupwithdrew, as did 10 assigned to inhaled zanamivir and 10 assignedto inhaled and intranasal zanamivir. The most common reasonfor withdrawal was failure to return for the scheduled studyvisits.
The use of relief medications was common. The cumulative frequencyof the use of acetaminophen (76 percent in the placebo group,76 percent in the group given inhaled zanamivir, and 74 percentin the group given intranasal and inhaled zanamivir), coughmedications (64 percent, 54 percent, and 52 percent, respectively),and decongestants (48 percent, 57 percent, and 40 percent) didnot differ significantly during the treatment period.
Clinical Efficacy
For the 262 patients with confirmed influenza, the median timeto the alleviation of major symptoms was five days in the placebogroups in both trials. This time was one day shorter in thegroups assigned to inhaled zanamivir (P=0.05) and intranasaland inhaled zanamivir (P=0.02). By the third study day the proportionof patients whose illness was alleviated was higher in the zanamivirgroups than in the placebo group, and this difference was maintainedafter the cessation of treatment (Figure 1). No obvious differenceswere noted between the zanamivir groups.
Figure 1. Alleviation of Symptoms in Patients Infected with Influenza A or B Virus Who Were Treated with Inhaled Zanamivir, Intranasal and Inhaled Zanamivir, or Placebo.
Alleviation of illness was defined as the absence of feverishness and the presence of no symptoms of headache, muscle aches, sore throat, and cough, or only mild ones, for at least 24 hours. As the P values indicate, the two zanamivir groups differed significantly from the placebo group but not from each other.
Analysis of the intention-to-treat population revealed findingssimilar to those for the infected population, although the sizeof the treatment effects was smaller (Table 2). No evidenceof benefit was observed in uninfected patients (data not shown).Further modeling analyses indicated that zanamivir was moreeffective in patients treated early, within 30 hours after theonset of symptoms (P=0.02 for the interaction with treatment),and in patients who were febrile at entry (P=0.05 for the interactionwith treatment). There was no evidence of a difference in thetreatment effect between type A and type B influenzavirus infectionsor between study locations (North America vs. Europe). Placeborecipients with documented fever on enrollment had more prolongedillness, and the median time to the alleviation of symptomsin this subgroup was two days longer than for the placebo-treatedpatients as a whole (Table 2). Among febrile patients who receivedzanamivir, symptoms were alleviated a median of three days soonerthan in the placebo group (P=0.01 for the comparison of placebowith inhaled zanamivir; P=0.001 for the comparison of placebowith intranasal and inhaled zanamivir). In addition, the febrilezanamivir recipients resumed their normal activities a medianof one day sooner than the febrile placebo recipients (Table 3).Those without fever on enrollment had no significant benefitof treatment (Table 2).
Table 3. Times to the Resumption of Usual Activities.
Among patients who were treated earlier in the course of illness(<30 hours after the onset of symptoms), who representedhalf of the enrolled influenza-infected population, the administrationof zanamivir was associated with a shorter — by threedays — median time to the alleviation of symptoms thanin the placebo group (P=0.001 for the comparison of placebowith inhaled zanamivir; P<0.001 for the comparison of placebowith intranasal and inhaled zanamivir). The cumulative fractionwhose symptoms were alleviated increased steadily, so that approximately90 percent had no symptoms or only mild ones through day 9 (Figure 2).In comparison, symptoms were alleviated more slowly in theplacebo recipients, and nearly 30 percent had not reached thisend point by day 10. The patients who were treated earlier withzanamivir resumed their normal activities a median of one totwo days before the respective placebo group (Table 3). In contrast,those treated more than 30 hours after the onset of symptomshad no significant reductions in these measures (Table 2 andTable 3).
Figure 2. Alleviation of Symptoms in Patients Infected with Influenza A or B Virus Who Were Treated within 30 Hours after the Onset of Symptoms with Inhaled Zanamivir, Inhaled and Intranasal Zanamivir, or Placebo.
Alleviation of illness was defined as the absence of feverishness and the presence of no symptoms of headache, muscle aches, sore throat, and cough, or only mild ones, for at least 24 hours. As the P values indicate, the two zanamivir groups differed significantly from the placebo group but not from each other.
Cough was the most persistent individual symptom, lasting amedian of four days among placebo recipients and three daysamong zanamivir recipients. Recipients of intranasal zanamivirtended to have shorter periods of nasal congestion (median,two days) than the other groups (three days). The duration offever was relatively brief in all groups (median, two days),but this analysis was confounded by frequent use of antipyreticdrugs.
The incidence of complications of influenza for which antibioticswere prescribed was 12 percent in the placebo group, 8 percentin the group given inhaled zanamivir, and 8 percent in the groupgiven intranasal and inhaled zanamivir. Otitis media was diagnosedin 2 percent of influenza-infected patients, sinusitis in 3percent, bronchitis in 2 percent, and pharyngitis and tonsillitisin 2 percent.
Virologic Measures
Among infected patients, the median duration of viral sheddingtended to be shorter among those given inhaled zanamivir (fourdays) or intranasal and inhaled zanamivir (four days) than inthose given placebo (six days). In the group given inhaled andintranasal zanamivir, the titers of virus recovered in nasalwashings were lower by a mean of 2.1 log10 TCID50 per milliliteron the second treatment day and by 1.5 log10 TCID50 per milliliteron the fourth day as compared with placebo (P=0.05 for the comparisonwith placebo by analysis of the AUC). As expected, no reductionsin nasal viral titers were noted in the group given inhaledzanamivir. None of the groups had increases in viral titersafter the cessation of therapy.
Among the infected patients, the frequencies of increases inantibody titers of fourfold or greater on hemagglutination-inhibitiontesting did not differ among the placebo group (53 percent ofpatients), the group given inhaled zanamivir (64 percent), andthe group given intranasal and inhaled zanamivir (56 percent).Similarly, the mean (±SD log2) increase in titers inpaired samples on hemagglutination-inhibition testing did notdiffer among the groups (2.2±1.6, 2.4±1.4, and2.1±1.8, respectively).
Tolerance
Six patients in each group withdrew during treatment. The numbersof patients who missed four or more doses because of noncomplianceor withdrawal were also similar in the three groups (13 patientsin the placebo group and 8 each in the group given inhaled zanamivirand intranasal and inhaled zanamivir).
Possible drug-related adverse events were reported by 18 percentof 144 patients assigned to placebo, 23 percent of 132 patientsassigned to inhaled zanamivir, and 25 percent of 141 patientsassigned to intranasal and inhaled zanamivir. During drug administration,adverse events related to the upper respiratory tract (9 percentof patients given placebo, 7 percent of those given inhaledzanamivir, and 11 percent of those given intranasal and inhaledzanamivir) or gastrointestinal tract (5 percent, 7 percent,and 9 percent, respectively) were the most common, but thesereactions were difficult to distinguish from symptoms due tothe underlying illness. The frequencies of local irritationof the nose (5 to 6 percent) or eyes (<1 percent) were similarin the three groups. No drug-related effects on blood counts,blood chemical values, or urinalysis results were found (datanot shown).
Discussion
The results of these studies show that administration of thenovel neuraminidase inhibitor zanamivir directly to the respiratorytract is associated with significant clinical and antiviraleffects in adults with naturally occurring influenzavirus infections.The magnitude of the observed clinical benefit was a one-day(approximately 20 percent) reduction in the time to the alleviationof major influenza symptoms. However, the degree of benefitwas greater in those with more pronounced illness, as indicatedby the presence of fever at enrollment, and in those treatedwithin 30 hours after the onset of symptoms. In these groupsthe median times to the alleviation of influenza symptoms wereapproximately 40 percent less (shorter by three days) than thatin the respective placebo group. These findings are consistentwith the relatively rapid resolution of uncomplicated influenzain previously healthy adults and the need for early antiviraldrug administration. The magnitude of the clinical benefit observedin this study appears to be at least as great as that in earliertrials of amantadine and rimantadine for acute febrile influenzaA illness in adults.17,18,19,20 In addition, as predicted bythe results of in vitro studies,8,9 tests in animal models,8,10and experimental studies in humans,21 the antiviral spectrumand clinical effectiveness of zanamivir included influenza Bvirus infections.
As expected, zanamivir was of no benefit in persons withoutlaboratory-documented influenzavirus infection. Although theclinical diagnosis of typical influenza in adults is highlypredictive of virologically confirmed infection during briskepidemics, in our study a relatively high proportion of enrolledpatients did not have confirmed influenza. This observationindicates the limitations of this approach and the need forrapid viral diagnosis when the likelihood of infection is nothigh.
Topical zanamivir was generally well tolerated, and the frequencyof local irritation was low. One source of concern was thatthe inhalation of dry powder would prove to be irritating inthose with acute influenza, which can cause mucosal damage andairway hyperreactivity.12 Although we did not measure pulmonaryfunction, the more rapid resolution of cough in recipients ofzanamivir than in placebo recipients is reassuring. Furthermore,previous studies of uninfected patients with asthma found noevidence of clinical intolerance or spirometric deteriorationafter multiple-dose inhalations of zanamivir for two weeks.22Because of the severity of influenza in patients with underlyingdisease of the airways (such as asthma, chronic bronchitis,emphysema, or cystic fibrosis) and the anticipated use of ananti-influenza agent in these high-risk patients, it will beimportant to collect further safety data in such patients. Theadministration of zanamivir did not impair the humoral immuneresponse to infection in our patients.
Intranasal zanamivir did not significantly enhance the clinicalbenefit observed with inhaled drug alone. However, this studywas not designed to detect differences between the zanamivirgroups, so it is premature to conclude that intranasal dosingwas not beneficial. For several outcome measures, the groupgiven both intranasal and inhaled zanamivir tended to benefitmore than the patients given placebo, even though the formergroup had a higher proportion of smokers and smoking is a riskfactor for more severe influenza.23 Intranasal zanamivir alsoreduced viral titers in the upper respiratory tract. Althoughthis was not tested directly in this study, such reductionsmight reduce the risk of transmission of influenzavirus. Sustainedantiviral effects in the nasal passages would probably be requiredto reduce the likelihood of local complications such as otitismedia and sinusitis. In this regard, the number of complicationsleading to the use of antibiotics tended to be lower in thezanamivir groups than in the placebo group, but our sampleswere too small to detect significant differences in these relativelyinfrequent events.
The patterns of drug deposition are not well characterized withthe delivery devices used in these trials. Previous studieshave shown broader distribution within the nasal passages ofmaterials administered by intranasal drops than by coarse sprays.24,25This difference in distribution is associated with less pronouncedantiviral effects of aerosolized agents than of drops in experimentalinfluenza11 and rhinovirus26 infections. Similarly, inhalationsmust be carefully administered to reach the lower airways andavoid being deposited on the oral mucosa or posterior pharynx.Our patients gave themselves the study drugs, which probablyresulted in suboptimal delivery of zanamivir in some cases.Consequently, it remains uncertain whether the effects observedin our study represent the maximal benefits that might be derivedfrom antiviral treatment of acute influenza with zanamivir.However, our findings indicate that topically applied zanamiviris an effective therapy for uncomplicated influenzavirus infectionsin adults, especially when initiated early. Pharmacologic inhibitionof influenzavirus neuraminidase may prove to be a useful therapeuticstrategy.
Drs. Hayden, Treanor, Aoki, and Nicholson have served as adhoc consultants to Glaxo Wellcome.
* The members of the GG167 Influenza Study Group are listed inthe Appendix.
Source Information
From the University of Virginia, Charlottesville (F.G.H.); Erasmus University, Rotterdam, the Netherlands (A.D.M.E.O., A.M.B.); University of Rochester, Rochester, N.Y. (J.J.T.); the Northfield Health Centre, Birmingham, United Kingdom (D.M.F.); University of Manitoba, Winnipeg, Canada (F.Y.A.); University of Leicester, Leicester, United Kingdom (K.G.N.); Glaxo Wellcome, Research Triangle Park, N.C. (H.M.H.); and Glaxo Wellcome, Greenford, United Kingdom (O.K., K.W.).
Address reprint requests to Dr. Hayden at Box 473, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
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Appendix
The following are members of the GG167 Influenza Study Group:Belgium: G. Adam, Brussels; H. Van Pottelbergh, Buizingen; M.Godefroid, Marche-on-Famenne; Finland: O. Ruuskanen and M. Makela,Turku; France: A. Simmons, Linas; J. Luciani, Coligny; J. Richir,Lille; J.A. Cozic, Nantes; M. Behar, Longpont sur Orge; Germany:R. Lehm, Stolpen; Italy: F. Pregliasco, Milano; P. Crovari,Genova; the Netherlands: A. Osterhaus, R. De Groot, A. Bohnen,P. Rothbarth, E. Claas, G. Rimmelzwaan, and J.C. van der Woude,Rotterdam; Norway: H. Hauge, Eidsvaag; I. Hercz, Hoevik; K.Innvik, Fyllingsdalen; M. Haegde Naess and O. Sand, Oslo; T.Tomassen, Trondheim; Spain: C. Jane and J.M. Bordas, Barcelona;M. Palomo, M. Alonso, and M.A. Villanueva, Madrid; Sweden: T.Sandberg, Goteberg; C. Ahlm, Umea; K. Pauksens, Uppsala; M.Glimaker, Danderyd; United Kingdom: D.M. Fleming, Birmingham;M.F. Duffy, Liverpool; D.S.A. Khan, Coppull; K. Nicholson, Leicester;Canada: F. Aoki, P. Orr, Winnipeg, Man.; B. Clecner, St. Jerome,Que.; J. Dylewski, Montreal; K. Forward, Halifax, N.S.; L.J.Miedzinski, Edmonton, Alta.; S. Walmsley, Toronto; K. Williams,Saskatoon, Sask.; D.E. Zoutman, Kingston, Ont.; United States:J. Adelglass, R.C. Andruczk, Dallas; S. Becker, Houston; S.Campbell, Tucson, Ariz.; V.A. Elinoff, Endwell, N.Y.; L.A. Fischer,West Palm Beach, Fla.; L.I. Gilderman, Pembroke Pines, Fla.;A. Graff, Fort Lauderdale, Fla.; F. Hayden and M. Lobo, Charlottesville,Va.; D. Henry, Sandy, Utah; T.M. Howard, Fort Belvoir, Va.;B. Kerzner and K.H. Williams, Baltimore; R. Kobayashi, Omaha,Nebr.; D.J. Mikolich, Providence, R.I.; J. O'Rourke and J. Rubino,Raleigh, N.C.; S.A. Pace, Fort Lewis, Wash.; L.E. Payne, LakelandAFB, Tex.; G.L. Post, Englewood, Colo.; A. Puopolo, Milford,Mass.; J. Rhudy, Salt Lake City; G.E. Ruoff, Kalamazoo, Mich.;J. Ryder-Benz, Cedar Rapids, Iowa; J. Schoenberger, RedwoodCity, Calif.; H.M. Serfer, Hollywood, Fla.; B.M. Sklar, Alameda,Calif.; W. Sun, El Paso, Tex.; J. Treanor, Rochester, N.Y.;W. Whitlock, Fort Gordon, Ga.
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